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Large Scale Non-targeted Metabolomic Profiling of Serum by Ultra Performance Liquid Chromatography-Mass Spectrometry UPLC-MS
Published on: March 14, 2013
Optimized UPLC-MS/MS Method for the Simultaneous Quantification of Pazopanib and GSK-1268997 and Its Application to
Lu Cao1,2, Peiqi Wang1, Ruibin Li1
1Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Introduction:
Pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), is approved for treating advanced renal cell carcinoma (RCC). However, pazopanib can cause hypertension, often necessitating co-administration with antihypertensives like nicardipine. Given their shared metabolic pathway via cytochrome P450 3A4 (CYP3A4), this study investigated their potential drug-drug interaction (DDI).
Methods:
An ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous quantification of pazopanib and its metabolite, GSK-1268997. This method was applied to in vitro inhibition studies using rat liver microsomes (RLM) and human liver microsomes (HLM), as well as to an in vivo pharmacokinetic study in rats, to evaluate the impact of nicardipine on pazopanib metabolism.
Results:
The assay was linear over the concentration ranges of 20-60,000 ng/mL for pazopanib and 10-30,000 ng/mL for GSK-1268997. The intra- and inter-day precision (relative standard deviations, RSD%) for the analytes ranged from 1.5% to 14.5%, with accuracy (relative errors, RE%) within ± 10.2%. The method also demonstrated acceptable selectivity, stability, matrix effect, and recovery. In vitro, nicardipine inhibited the metabolism of pazopanib in both RLM and HLM. In rats, co-administration of nicardipine significantly increased pazopanib exposure. The AUC(0-t) and AUC(0-∞) of pazopanib were increased by 4.03- and 4.31-fold, respectively, while the maximum plasma concentration (Cmax) was increased by 1.60-fold. Conversely, the plasma clearance (CLz/F) was decreased by 78.26%.
Discussion:
The findings demonstrated that nicardipine significantly inhibited the metabolism of pazopanib both in vitro and in vivo, leading to substantially increased systemic exposure of pazopanib. This clinically significant finding suggests that, when these two drugs are used in combination, plasma drug concentrations should be closely monitored and the need for dose adjustment should be considered.
Insights
Nicardipine significantly inhibits pazopanib metabolism, increasing its systemic exposure. Close monitoring of pazopanib concentrations and potential dose adjustments are recommended when co-administering these drugs.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacology
Background:
- Pazopanib, a VEGFR-TKI, treats advanced renal cell carcinoma (RCC).
- Pazopanib can cause hypertension, often requiring co-administration with antihypertensives like nicardipine.
- Both drugs share the CYP3A4 metabolic pathway, raising concerns for drug-drug interactions (DDIs).
Purpose of the Study:
- To investigate the potential drug-drug interaction (DDI) between pazopanib and nicardipine.
- To evaluate the impact of nicardipine on pazopanib metabolism in vitro and in vivo.
Main Methods:
- Developed and validated an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantifying pazopanib and its metabolite GSK-1268997.
- Conducted in vitro inhibition studies using rat liver microsomes (RLM) and human liver microsomes (HLM).
- Performed an in vivo pharmacokinetic study in rats to assess nicardipine's effect on pazopanib metabolism.
Main Results:
- Nicardipine demonstrated significant inhibition of pazopanib metabolism in both RLM and HLM.
- In rats, co-administration with nicardipine led to a 4.03- to 4.31-fold increase in pazopanib exposure (AUC) and a 1.60-fold increase in Cmax.
- Plasma clearance of pazopanib decreased by 78.26% in the presence of nicardipine.
Conclusions:
- Nicardipine significantly inhibits pazopanib metabolism, leading to substantially increased systemic exposure.
- Clinical monitoring of pazopanib plasma concentrations and consideration of dose adjustments are crucial when co-administering with nicardipine.
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